The overall aim of the proposed research is to examine aortic histamine metabolism, especially histamine synthesis, in rats following induction of diabetes mellitus by subtotal pancreatectomy, in an attempt to gain insight into (1) intrinsic systems regulating large vessel transmural permeability, and (2) reasons for the well known increased susceptibility of diabetics to atherosclerosis. Underlying the entire scope of the proposed research are the assumptions that vascular injury is a primary causative factor in the pathogenesis of atherosclerosis, that hyperglycemia has the potential of inducing such injury, that aortic transmural permeability is influenced by intrinsic aortic histamine synthesis, and that the initial arterial lesion of atherosclerosis may in part represent a prolonged inflammatory response mediated by aortic histidine decarboxylase. It is believed that local induction of histamine synthesis may represent an important process whereby altered vascular states are translated into subsequent increases in aortic permeability. The specific aims of the proposed research may be summarized as follows. First, normal values will be established for the histidine decarboxylase system in selected regions of the aortic wall. Second, histamine metabolism, with specific attention given to synthetic pathways in these preparations, will be examined following attainment of diabetes, as determined by the overall glucose intolerance shown by animals subjected to the above surgical procedure. Finally, these metabolic changes will be correlated with changes in aortic wall permeability and endothelial integrity through the use of quantitative dye markers and histological examination of tissue sections, as well as with changes in circulating insulin.